(M-087) An Integrated PK-PD Model to Characterize Circadian-Driven ACTH-Cortisol Interactions in Patients with Congenital Adrenal Hyperplasia

Diqin Yan – Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN; Mutaz Jaber – Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN; Wenxi Liu – Department of Physical Education, Shanghai Jiao Tong University, Shanghai, CN; Zan Gao – Department of Kinesiology, Recreation, and Sport Studies, The University of Tennessee, Knoxville, TN; Yesica Munoz – Division of Pediatric Endocrinology, University of Minnesota Medical School, Minneapolis, MN; Stafford Lightman – Laboratory for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom; Megan Gunnar – Institute of Child Development, University of Minnesota, Minneapolis, MN; Richard Brundage – Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN; Kyriakie Sarafoglou – Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN; Shen Cheng – Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN

Objectives: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a primary adrenal insufficiency characterized by impaired cortisol synthesis and disruption of the negative feedback loop of hypothalamic-pituitary-adrenal (HPA) axis resulting in increased adrenocorticotropic hormone (ACTH). Excess ACTH drives the accumulation of cortisol precursors, which are shunted into the androgen pathway, leading to excess androgen production1. Oral hydrocortisone (HC) is the recommended glucocorticoid for children given in 3 doses (10-15 mg/m2/d)2. However, clinical outcomes remain suboptimal due to limitations of HC treatment: 1) short half-life (41-105 minutes); 2) substantial PK/PD variability3; 3) inability to replicate physiological circadian-driven hormone patterns4. As a result, patients are exposed to alternating periods of hypo- and hypercortisolemia, associated with adverse outcomes5. To address these challenges, we developed an integrated PK-PD model that simultaneously characterizes the dynamic interactions between total cortisol and ACTH following HC dosing in CAH patients.

Methods: Concentration-time profiles for cortisol and ACTH were obtained from two clinical studies: 1) a phase III clinical trial that collected 24-h profiles (25 sampling time points) in 9 CAH children to compare the effectiveness of HC administered orally versus via a pulsatile subcutaneous (SQ) pump6; and 2 ) a PK study that collected 6-h post-dose profiles (12 sampling time points) from 69 CAH patients following oral HC dosing.
Exogenous cortisol disposition was described using a one-compartment model with first-order elimination. Two first-order processes described the HC absorption following oral or SQ pump dosing. Indirect response models characterized the dispositions of ACTH and endogenous cortisol. Michaelis-Menten equations described the stimulatory effect of ACTH on endogenous cortisol production and the inhibitory effect of cortisol on ACTH secretion. Both dual cosine functions and surge functions were implemented on KinACTH to characterize the circadian hormone dynamics. Between-subject variability assumed log-normal distributions. Residual variability was described using proportional error models. Model fittings were evaluated by objective function values, statistical and biological plausibility of parameter estimate and precision, and goodness-of-fit plot. Estimation was executed using IMP in NONMEM v7.5.0.

Results: The developed cortisol/ACTH model adequately described the observed data. Goodness-of-fit plots and objective function values suggested surge function to be superior in capturing the circadian hormone dynamics than dual cosine function. Cortisol clearance was 23.2 L/h/70 kg (95% CI: 15.5-30.9). The cortisol and ACTH concentrations producing 50% of the maximal response (IC50 and EC50) were 3.24 ug/dL (95% CI: 2.79-3.69) and 23.0 pg/mL (95% CI: 12.7-33.3), respectively.

Conclusions: The integrated PK-PD model sufficiently characterized the disposition and dynamic interactions of cortisol and ACTH following HC dosing in patients with CAH, while accounting for circadian rhythm. It may support clinical decision-making by guiding HC dosing in this population.

Citations: 1. Sarafoglou K, Merke DP, Reisch N, Claahsen-van der Grinten H, Falhammar H, Auchus RJ. Interpretation of Steroid Biomarkers in 21-Hydroxylase Deficiency and Their Use in Disease Management. J Clin Endocrinol Metab. Aug 18 2023;108(9):2154-2175. doi:10.1210/clinem/dgad134
2. Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. Nov 1 2018;103(11):4043-4088. doi:10.1210/jc.2018-01865
3. Sarafoglou K, Zimmerman CL, Gonzalez-Bolanos MT, Willis BA, Brundage R. Interrelationships among Cortisol, 17-Hydroxyprogesterone, and Androstenendione Exposures in the Management of Children with Congenital Adrenal Hyperplasia. J Investig Med. 2015/01/01 2015;63(1):35-41. doi:10.1097/JIM.0000000000000121
4. Peters CJ, Hill N, Dattani MT, Charmandari E, Matthews DR, Hindmarsh PC. Deconvolution analysis of 24-h serum cortisol profiles informs the amount and distribution of hydrocortisone replacement therapy. Clin Endocrinol (Oxf). 2013;78(3):347-351. doi:https://doi.org/10.1111/j.1365-2265.2012.04502.x
5. Al-Kofahi M, Ahmed MA, Jaber MM, et al. An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia. Br J Clin Pharmacol. 2021;87(3):1098-1110. doi:https://doi.org/10.1111/bcp.14470
6. ClinicalTrial. Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia. Accessed Feb 3, 2025, https://clinicaltrials.gov/study/NCT03718234?cond=Congenital%20Adrenal%20Hyperplasia&intr=pump&rank=4

Keywords: Congenital Adrenal Hyperplasia, hypothalamic-pituitary-adrenal axis, circadian rhythm modeling